17beta-hydroxy-17alpha-halohydrocarbon-19-nor-androst-4-ene-3-ones and the delta5(10)-isomers thereof



United States Patent 175 HYDROXY 17a HALOHYDROCARBON 19- NOR-ANDROST- t-ENE-Zi-ONES AND THE A ISOMERS THEREOF John Fried, Palo Alto, Calif., and Thomas S. Bry, Linden, and Arthur A. Patchett, Cranford, NJ., assignors to Merck & C0., Inc., Rahway, NJ., a corporation of New Jersey No Drawing. Filed Oct. 18, 1965, Ser. No. 497,464

19 Claims. (Cl. 260-2395) This is a continuation-in-part of Ser. No. 142,776, filed Oct. 4, 1961.

This invention is concerned generally with novel steroid compounds and processes for preparing the same. More particularly, it relates to novel l7,B-hydroxy-17ahalohydrocarbon l9 nor-androst-4-ene-3-ones and the A isomers thereof, and to closely related compounds, in particular the l7fi-ethers thereof such as the l7B-alkyl, 17,8-cycloalkyl, l7fi-arallcyl ethers, l7B-unsaturated hydrocarbon ethers .and 17/3 basically substituted alkyl ethers, and the 17,8-acyl esters thereof such as l7B-alkanoyl esters and 17,8-alkanoyl esters and 17B-alkyl carbonates.

The compounds prepared by this invention are valuable as orally and parenterally active progestational agents, which also have the property of inhibiting gonadotropin secretion. The compounds are useful in the treatment of various human ailments requiring progestational hormone therapy as well as in the synchronization of the estrus in the domestic animals.

The products of this invention may be represented by the structural formulae:

wherein R is hydrogen, aralkanoyl, alkanoyl, aralkyl, alkyl, cycloalkyl, an unsaturated .aliphatic radical, and a substituted amino alkyl radical, Y is an unsaturated halohydrocarbon radical having 2 to 3 carbon atoms.

In preparing our novel chemical compounds, the starting material utilized is the 3-methoxy-19-nor-2,5(10)- androstadiene-17-one, which has the following structural 3,340g25 l Patented Sept. 5, 1967 ice oxy-19-nor-2,5(10)-androstadiene which has the following structural formula:

wherein Y is selected from the group consisting of trifluorovinyl, trifiuoromethylvinyl and trifluoromethylethynyl by reaction with a strong mineral acid, such as 3 p-toluenesulfonic acid. For example, a mixture of the steroid and .p-toluenesulfonic acid in acetone solution is left standing at room temperature for about 18 hours.

The Not-substituted 175-hydroxy-19-nor-4-androstene- 3-one and the Not-substituted 17B-hydroxy-l9-nor-5 (10)- 3 androstene-3-one are converted into the 17/3-alkanoyl ester by reaction with an alkanoic acid anhydride or alkanoyl halide in the presence of a tertiary amine such as pyridine. The acid anhydrides which may be used for this purpose include acetic anhydride, propionic anhydride, butyric anhydride and the like. The 17,3-caproate is prepared by the reaction of the 17fi-free alcohol with caproyl halide in the presence of a tertiary amine base.

The 17,8-substituted 3 -methoxy-19-nor-2,5 10) -androstadiene-l7B-ol is converted into the flat-substituted 17,8- hydroxy-19-nor-5(l0)-androstene-3-one which has the following formula:

wherein Y is as above by reaction with a weak organic acid such as acetic acid. For example, a mixture of the steroid and glacial acetic acid and sodium acetate in an aqueous solution of absolute ethanol and tetrahydrofuran is left standing at room temperature for several hours.

Useful and novel compounds within the scope of the present invention which may be prepared by this process include 3 l7a-trifluoromethylvinyl-17,3-hydroxy-l9-nor-5 -androstene-3-one-17B-caproate and l7a-trifiuoromethylethylnyl-l7/3-hydroxyl9-nor-5 10) androstene-3 -one-17 3-va1erate.

The 17a-halo hydrocarbon-17B-hydroxy-l9-nor-androstene-3-ones of this invention are readily converted into the corresponding l7fi-aralkyl, N B-alkyl, 17,8-unsaturated aliphatic ethers and l718-substituted amino alkyl ethers by reaction when an aralkyl, an alkyl, a cycloalkyl, or unsaturated aliphatic or a substituted amino alkyl halide or sulfate and a base.

In one modification of this process the l7fl-hydroxy compound is reacted with an halide and silver oxide in 'a solvent such as a dialkyl alkanolylamide such as dimethyl formamide and the like to form the corresponding 17,6-ether. The alkyl halides which may be used for this purpose include methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, isobutyl iodide, amyl iodide, isoamyl iodide, hexyl iodide and the corresponding alkyl bromides. Also suitable are the cycloalkyl halides such as cyclopentyl iodide, cyclohexyl iodide, cyclopentyl bromide and cyclohexyl bromide and-aralkyl halides, suitably benzyl iodide. The unsaturated aliphatic halides such as allyl bromide and cyclohexenyl iodide as well as the substituted amino alkyl halides such as diethyl amino ethyl bromide, pyrrolidyl ethyl bromide and morpholino propyl bromide may also be used.'

The steroid alcohol, for example 17 -trifluoromethylvinyl-l7 3-hydroxy-19 nor-4-androstene-3-one is mixed with the solvent, for example dimethyl formamide in the presence of the alkyl halide such as ethyl iodide, and silver oxide is added. The mixture is stirred at from about 10 to about 80 C. for from 2 to 6 days, from to 30 C. for 4 days being preferred, a small amount of silver oxide being added each day. The product is then isolated. In one mode of isolation a reaction inert, water immiscible solvent, for example a halogenated hydrocarbon solvent suitably chloroform is added to the reaction mixture which is then stirred and filtered. The solvent is removed from the filtrate preferably by evaporation under reduced pressure and the residue chromatographed.

In an alternative method of preparation, the 17 8-hydroxy steroid may be taken up in a reaction inert organic solvent, such as an aromatic hydrocarbon solvent, for example, benzene or toluene, and treated with an aliphatic halide, any of the aralkyl, alkyl, cycloalkyl, unsaturated aliphatic and substituted amino alkyl listed in the above.- mentioned modification of the process being suitable, in the presence of an alkali metal hydride such as sodium or potassium hydride to produce the 17fi-ether.

The steroid alcohol, for example l7a-trifiuoromethylethynyl-l7B-hydroxy-l9-nor-4-androstene 3 one is dissolved ina reaction inert organic solvent, for example, benzene, and the aliphatic halide, for example cyclopentyl iodide in benzene is added. A small excess of halide is used. The alkali metal hydride, suitably sodium hydride is then suspended in the same solvent and added to the mixture. The mixture is then agitated for from about 1 to about 36 hours at a temperature of from about 10 to 80 C., agitation for 18 hours at from 15 -30 C. being preferred. The product is then isolated. In one suitable method of isolation, water is added to the mixture to destroy any remaining alkali metal hydride and the mixture extracted with a reaction inert water immiscible solvent such as benzene or ether. The organic extract is dried over a suitable drying agent, such as potassium carbonate and filtered. The solvent is then removed, suitably by evaporation under reduced pressure to yield the desired product as a residue which may be further purified by chromatography.

In yet another modification of the process, the 17 8- hydroxy steroid is reacted with an aryl or alkyl alkali metal salt such as methyl lithium, butyl lithium or phenyl lithium to produce a corresponding 17,8-oxy lithium salt which is then treated with an aralkyl, alkyl or cycloalkyl halide. Any of the halides utilized in the previous modification of this process being suitable to produce the desired l7fi-aralkoxy, 17fl-alkoxy or l7B-cycloalkloxy steroid.

The steroid alcohol, for example l7a-trifiuoromethylvinyl-17,8-hydroxy-l9-nor-5 10) -androstene-3-one is taken up in an ether, diethyl ether, or tetrahydrofuran being preferred. A solution of an aryl or alkyl alklai metal salt suitably phenyl lithium or butyl lithium in ether or tetrahydrofuran is then added. The mixture is then agitated for from about l -to about 4 hours at from about 10 to about 30 C.,'in an inert atmosphere, a nitrogen atmosphere being prefered. A solution of the aralkyl, alkyl or cycloalkyl halide in a similar solvent, for example ether or tetrahydrofuran is then added and the mixture agitated at from about 10 to about 60 C. for a further period of from about 10 to about 24 hours, agitation at about 15 to about 30 C. for about 18 hours being especially suitable. The product is then isolated, suitably a saturated brine solution is added and the mixture extracted with a water immiscible solvent such as benzene or ether. The

organic extract is then dried over a suitable drying agent such as sodium sulfate, filtered and the solvent removed, preferably by evaporation under reduced pressure. The residue containing the desired product may be further purified by chromatography.

In another modification of the process the 17B-hydroxy steroid, for example Nor-trifluorovinyl-17fi-hydroxy-l9- nor-5(10)-androstene-3-one is treated with a dihydrocarbon sulfate in an aqueous alkaline medium to produce the corresponding steroid 17;? ethers. The dialkyl, diaralkyl and dicycloalkyl sulfates which may be used in this modification include, for example dimethyl sulfate, diethyl sulfate, dipropyl sulfate, diisopropyl sulfate, dibutyl sulfate, diisobutyl sulfate, diamyl sulfate, diisoamyl sulfate, dihexyl sulfate, dibenzyl sulfate, dicyclopentyl sulfate, dicyclohexyl sulfate, and the like. Sodium or potassium hydroxide in aqueous solution are preferred as the alkaline medium.

The steroid alcohol for example, l7u-trifluoromethylethynyl-17B-hydroxy-19-nor-5 (l0) androstene-3-one is taken up in a reaction inert solvent such as benzene, toluene, ether or tetrahydrofuran and added to a mixture of the dialkyl sulfate in the aqueous alkaline medium. It is preferred to use a small excess of the dialkyl sulfate, a molar excess of about 5% to about 20% being suitable. The mixture is then allowed to stand for from 1 to 24 hours at a temperature of from about 10 to about 80 C., however it is preferred to allow the mixture to stand for about 18 hours at. about 15 to about 30 C. Where the solvent utilized is substantially immiscible with the aqueous medium it is preferred to agitate the mixture during the reaction time. The product is then isolated. In one method of isolation the mixture is extracted with a reaction inert water immiscible solvent such as benzene or toluene. The extract is then dried over a drying agent for example over potassium carbonate, filtered and the solvent removed, suitably by evaporation under reduced pressure. The product is obtained as a residue which may be further purified by chromatography.

Useful and novel products Within the scope of the present invention which may be prepared by these processes include 17a trifluorovinyl 1*9 nor 4 a-ndrostene 3 one 17,8 methyl ether, 17cc trifluoromethylvinyl 19 nor 4 androstene 3 one 17B- ethyl ether, 17oz trifiuoromethylethynyl-l9-nor-4-androstene- 3-one-l7/8-propyl ether, l7a-trifiuorovinyl-19-nor-5 3-one-17B-benzyl ether and 17-u-trifluoromethylethynyl-l9- nor-5(10)-androstene-3-one 17fi-benzyl ether, 17oc-t1iflu'0- rovinyl-19-nor-4-androstene-3brie-176 allyl ether, 17atrifluoromethylvinyl-l9-nor-5(10) androstene-3-one175- cyclohexenyl ether, 17a-trifluoromethylethynyl-19-nor-4- androstene-3-one-17fl-diethylamino ethyl ether, 17 a-UiflllO- romethyl vinyl-l9-nor-5(10) androstene 3-one-l7 3-pyrrolidyl ethyl ether and l7u-trifluoromethylethynyl-l9-nor- 4-androstene-3-one-17B-morpholino propyl ether.

The compounds of this invention may be administered alone or associated with a pharmaceutical carrier, choice of which depends upon the properties of the active compound and standard pharmaceutical practice. Generally the compound is administered in dosages of the same order of magnitude as other progestational agents such as Norethisterone and dosage units may take the form of tablets, powders, capsules, elixirs, or syrups which are particularly useful for oral ingestion. Liquid diluents are employed as a condition for parenteral use.

The following examples are given by way of illustration only and are not intended as a limitation of this invention, many apparent variations of which are possible without departing from the invention and scope thereof.

EXAMPLE 1 500 cc. three-neck round bottom flask is fitted with a Dry Ice condenser, a dropping funnel and a magnetic stirrer. After the addition of 4.0 g. of magnesium, the entire system is swept with nitrogen and flame dried. One hundred cc. of dry tetrahydrofuran is added to the magnesium and 13 g. of trifluorovinyl bromide is bubbled into the solution held at 25 C. with stirring. The solution is decanted into a dry flask and stored. A solution of 500 mg. of 3-methoxy-2,5(l0)androstadiene-17-one which is dried by azeotropic distillation from benzene, is added in 5 cc. of benzene and 5 cc. of dry ether to 50 cc. of the triflorovinyl magnesium bromide solution prepared above. The reaction is stirred for 16 hours at room temperature. Water is then added and the mixture extracted with ether. The organic extracts are washed with water until the washings are weakly basic, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on 20g. of basic alumina, by charging with petroleum ether and eluting with a mixture of petroleum ether and ether to give 17a-trifluorovinyl-3-methoxy-2,5(10)-androstadiene-l7fl-ol.

Irr accordance with the above procedure but starting with trifiuoromethylvinyl bromide and trifluoromethylethynyl bromide in place of triflurovinyl bromide there is obtained 17a. trifluoromethylvinyl 3-rnethoxy-19-nor- 2,5(l)-androstadiene-17fi-ol and 170: trifiuoromethylethynyl-3-methoxy-l9-nor-2,5 (10) androstadiene-17fi-ol.

EXAMPLE 2 To 150 mg. of the product obtained in Example 1, in 15 cc. of acetone is added 15 mg. 'of paratoluenesulfonic acid. This mixture is allowed to stand for 18 hours at room temperature, and is then poured into ice water and extracted with ether. The organic extracts are washed to neutrality with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on g. of acid-washed alumina by charging with benzene and eluting with 6 parts of a mixture of petroleum ether with 4 parts of ether. Recrystallization from a mixture of petroleum ether and ether afiords. 17a-trifluorovinyl-l7fllhydroxy-l9-nor-4-androstene-3-one.

In accordance with the above procedure but starting with l7a-trifluoromethylvinyl-3 -methoxy-19-nor-2,5 androstadiene-l7,6-ol and 17a: trifluoromethylethynyl-Frmethoxy-19-nor-2,5(lO)-androstadiene-17fi-ol in place of 17a-triiiuorovinyl-3-methoxy l9-nor-2,5(10)-androstadiene-l7 3-ol there is obtained 17a-trifluoromethylvinyl-17B- hydroxy-l9-nor-4 androstene-3-one, and l7a-trifluoromethylethynyl-l7B-hydroxy-19-nor-androstene-3-one.

6 EXAMPLE 3 To 410 mg. of 17a-trifluorovinyl-3-methoxy-19-nor- 2,5 10)-androstadiene-17B-ol in 4.1 cc. of tetrahydrofuran and l8.45 cc. of absolute ethanol is added 8.2 cc. of glaclal acetic acid and 0.5 g. of sodium acetate in 4.1 cc. of Water. This reaction mixture is left stirring at room temperature for 5 hours. It is then poured into an ice-sodium bicarbonate solution and extracted with benzene. The benzene extract is washed with water until the washings are ust slightly basic, dried over sodium sulfate and concentrated in vacuo. The crude product is chromatographed on 40 g. of silica gel by charging with .a mixture of 1 part benzene and 1 part petroleum ether, and eluting with mixtures of petroleum ether and ether to yield 17u-t1'ifill010- vmyl-17,8-hydroxy-19-nor-5( l0 -androstene-3-one.

In accordance with the above procedure but starting with 17a-t1ifill0r0methYlVi1'lYl-19-I10r-3 -methoxy-2,5 10) androstadiene-17/8-ol and 17m-trifluoromethylethynyl-3- methoxy-l9-nor-2,5(10)-androstadienel7/3-ol in place of trifluorovinyl 3 methoxy-19-nor-2,5 (10)-androstadiene-17fi-ol there is obtained 17a-trifluoromethylvinyll7fi-hydroxy-19-nor-5(10)-androstene-3-one and 17a-trifluoromethylethynyl 17,8 hydroxy-19-nor-5(10)-androstene-3-one.

EXAMPLE 4 One hundred mg. of 17u-trifiuoroviny1-l7fl-hydroxy- 19-nor-4-androstene-3-one is heated with 1 cc. of acetic anhydride and 1.2 cc. of pyridine on the steam bath overnight. The reaction mixture is then poured onto ice and extracted with chloroform. The extract is washed with water and concentrated. The concentrate is chromatographed over acid-washed alumina and eluted with mixtures of ether and petroleum ether to give 17fi-acetoxyl'l'a-trifluorovinyl-l9-nor-4-androstene-3-one.

In accordance with the above procedure but starting with 17atrifiuorornethylvinyl-17fl-hydroxy 19 nor 4- androstene-S-one, l7a-trifluoromethylethynyl 17,8 hydroxy-l9-nor-4-androstene-3-one, 17a-trifluorovinyl-175- hydroxy-l9-nor-5(10)-androstene 3 one, 17a-triflu0romethylvinyl 17,6 hydroxy-l9-nor-5(l0)-androstene-3- one, and 17a-trifiuoromethylethynyl-17,8-hydroxy-19-nor- 5(l0)-androstene-3-one in place of 17a-trifiuorovinyl- 17fi-hydroxy-19-nor-4-androstene-3-one there is obtained 17/3-acetoxy 17o: trifluoromethylvinyl-19-nor-4-androstene-3-one, 17B-acetoxy-l7a-trifluoromethylethynyl l9- uor-4-androstene-3-one, 17,6 acetoxy-l7u-trifiuorovinyl- 19-nor-5 (10)-androstene-3-one, 17B-acetoxy 17a trifiuoromethylvinyl-19-nor-5 10)-androstene-3-one and 17/3- acetoxy-l7u-trifluoromethylethynyl 19 nor 5(10)- androstene-3-one.

In accordance with the above procedure but starting with any of the aforementioned 17B-hydroxy androstenes and using propionic anhydride, butyric anhydride and valeric anhydride in place of acetic anhydride there are obtained the corresponding l7ti-propionoxy, 17fi-butyroxy, and 17B-valeroxy androstenes.

EXAMPLE 5 One hundred mg. of l7oz-trifiuorovinyl-17,8-hydroxy-19- nor-4-androstene-3-one is heated with 1 cc. of caproyl chloride and 1.2 cc. of pyridine on the steam bath overnight. The reaction mixture is then poured onto ice and extracted with chloroform. The extract is Washed with water and concentrated. The concentrate is chromatographed over acid-washed alumina and eluted with mixtures of ether and petroleum ether to give l'lfi-caproyloxy- 17a-trifluorovinyl-19-nor-4-androstene-3-one.

In accordance with the above procedure but starting with l7u-trifluoromethylvinyl 176 hydroxy-19-nor-4- androstene-3-one, 17oz trifluoromethylethynyl-17fi-hydroxy-19-nor-4-androstene-3-one, l7a-trifiuorovinyl-l7 8- hydroxy-l9nor-5(10)-androstene-3-one, 17cc trifluoromethylvinyl 17,8 hydroxy-19-nor-5(10)-androstene-3- one, and 17u-trifiuoromethylethynyl-17fi-hydroxy-19-norcaproyloxy 17u-trifiuoromethylvinyl-19-nor-4-androstene- 7 3-one, 17B-caproyloxy-17a trifluoromethylethynyl-19-nor- 4-androstene-3-one, 17B-caproyloxy-17a-trifluorovinyl-19- nor-5 10) -androstene-3-one, 17,8-caproyloxy-17u-trifluoromethylvinyl-19-nor-5(10)-androstene 3 one and 175- caproyloxy-17 a-trifiuoromethylethynyl 19 nor 5(10)- androstene-B-one.

In accordance with the above procedure but starting With any of the aforementioned 17B-hydroxy androstenes and using benzoyl chloride, propionyl chloride, butyryl chloride, t-butylacetyl chloride and valeryl chloride in place of caproyl chloride there-are obtained the corresponding 17fi-benzoxy, 17/3-propionoxy, 17fl-butyroxy, 17p-t-butyl acetoxy, and l7B-valeroxy androstenes.

EXAMPLE 6 A mixture of 500 mg. of Nix-trifluorovinyl-17,8-hydroxy-l9-nor-4-androstene-3-one, 10 ml. of dimethyl formamide, 20 ml. of ethyl iodide, and 1.5 grams of silver oxide are stirred at room temperature for 4 days, an additional /2 gram of silver oxide being added at the end of each day. 100 ml. of chloroform is then added to the reaction mixture and the mixture is stirred for one hour and filtered. The filtrate is evaporated to dryness and the residual oil is chromatographed over acid washed alumina and eluted with mixtures of ether and petroleum ether to give 170: trifluorovinyl-19-nor-4-androstene-3one-17B- methyl ether.

In accordance with the above procedure but starting with 170: trifiuoromethylvinyl-l7 3-hydroxy-19-nor-4-androstene-3-one, 17a-trifluoromethylethynyl17[3-hydroxy- 19-nor-4-androstene-3-one, flea-trifluorovinyl 17B hydroxy-19-nor-5 10)-andr0stene-3-one, 17a-trifiuoromethylvinyl-l7B-hydroxy-19-nor-5 (10)-androstene-3-one and 17a-trifluoromethylethynyl 17,3 hydroxy-l9nor-5( l)- androstene-3-one in place of 17a-trifiu0rovinyl-l7B-hydroxy-19-nor-4-androstene-3-one there is obtained 170ctrifiuoromethylvinyl-l9-nor-4-androstene 3 one 17fi methyl ether, 17a-trifiuoromethylethynyl-l9-nor-4-androstene-3-one-l7B-methyl ether, 17a-trifluorovinyl-l9-nor- 10)-androstene-3 -one-l7/3-methyl ether, Not-trifluoromethylvinyl-l9-nor-5(10)-androstene-3-one 1713 methyl ether, and 17a trifluoromethylethynyl-19-nor-5(10)-androstene-3-one-17,6-methyl ether.

In accordance with the above procedure but starting with any of the aforementioned 17,6-hydroxy androstenes and using propyl, butyl, amyl, hexyl, cyclopentyl, cyclohexyl, allyl, cyclohexenyl, diethylamino ethyl, pyrrolidyl ethyl, morpholino ethyl, or benzyl iodide or bromide in place of methyl iodide there are obtained the corresponding 17B-ethoxy, 17,6-propoxy, 17,8-butoxy, 17,6-amoxy, 17B-hexoxy, 17B-cyclopentyloxy, 17fi-allyloxy, 1' 7;3-cyclohexenoxy, 17B-diethylamino ethoxy, 17p-pyrrol1dyl ethoxy, l7fl-morpholino ethoxy, and 17,8-benzyloxy androstenes.

EXAMPLE 7 To a mixture of 710 milligrams of l7a-trifiuoromethylvinyl-17j3-hydroxy-19'-nor-4-androstene-3-one and 20 ml. of cyclopentyl iodide in 100 milliliters of benzene are added a suspension of 5 gms. of sodium hydride in 20 milliliters of benzene and the mixture stirred at about 20 C. for 2 days under a nitrogen atmosphere. 100 milliliters of Water are then added to the mixture which is then stirred for a further hour. Theorganie layer is separated and the water layer extracted with benzene. The combined benzene extracts are then dried over anhydrous potassium carbonate, filtered, and evaporated under reduced pressure. The residue is then chromatographed over acid washed alumina and eluted with mixtures of ether and petroluem ether to give 17a-trifluoromet-hylvinyl-l9-nor-4-androstene-3-one-17/8-cyclopentyl ether.

In accordance with the above procedure but starting 8. with 17oZ-tr'ifluorovinyl-17 8-hydroxy-19-nor-4-androstenel 3-one, a trifiuoromethylethynyl 17B hydroxy 19-' nor-4-androstene-3-0ne, 1Lit-trifluorovinyl-17B-hydroxy4 19-nor-5 10) -androstene-3 -one, 17oc-tllflll0l'0l'l16thYlVlHYl- 17fi-hydroxy-l9-nor-5(10)-androstene-3-one and l7a-trifiuoromethylethynyl 17,3 hydroxy 19 nor 5(10)- androstene-3-one in place of 17u-trifluoromethylvinyl-,

17B-hydroxy-l9-nor-4-androstene-3-one there is obtained 17cc trifluorovinyl 19 nor 4 androstene 3 onel7 3-cyclopentyl ether, 17a-trifluoromethylethynyl-l9-nor- 4-androstene-3-one-17,8-cyclopentyl ether, Una-trifluorovinyl 19 nor 5(10) androstene 3 one 17,8 -cyclopentyl ether, 17a-trifluoromethylvinyl-19-nor-5 (10) androstene-3-one-17B-cycl0pentyl ether and l7a-tliflu0l'0- methylethynyl 19 nor 5(10) androstene 3 one- 17,B-cyclopentyl ether.

In accordance with the above procedure but starting with any of the aforementioned 17B-hydroxy androstenes and using methyl, ethyl, propyl, butyl, amyl, hexyl, benzyl and cyelohexyl iodide or bromide in place of cyclopentyl iodide there are obtained the corresponding 17fimethoxy, 17/3-ethoxy, l7B-propoxy, 17,3-butoxy, 17,3- amoxy, 17,8-hexoxy, l7 3-benzyloxy and 17,8-cyclohexoxy androstenes.

EXAMPLE 8 To a solution of 744 mg. of l7a-trifluoro'methylethynyl-17,6-hydroxy-l9-nor-4-androstene-3-one in 3,0 ml. of tetrahydrofuran is added a solution containing 2 gms. of phenyl lithium. The mixture is then stirred for 2 hours at 20 C. under nitrogen. A solution of 5 gms. of n-butyl iodide in 10 ml. of tetrahydrofuran is then added and the mixture stirred under nitrogen at 20 C. for a further 18 hours. The reaction mixture is then decomposed by the addition of a saturated aqueous solution of sodium chloride. The mixture is then thoroughly extracted with benzene and the organic extract dried over sodium sul fate, filtered, and evaporated under reduced pressure. The residue is then chromatographed over acid washed alumina and eluted with a mixture of ether and petroleum ether to give l7u-trifiuoromethylethynyl-l9-nor-4-andro, stene-3-one-l7fi-n-buty1 ether.

In accordance with the above procedure but starting with 17oz trifluoromethylvinyl 17p hydroxy 19 nor- 4 androstene 3 one, 17a trifluorovinyl 17B hydroxy-19-nor-4-androstene-3-one, 17a-trifluorovinyl-l7flhydroxy 19 nor 5(10) androstene 3 one, 170:- trifluoromethylvinyl 17B hydroxy 19 nor 5(10) androstene-3-one and 17u-trifiuoromethylethynyl-17,8-hydroxy-l9-nor-5(10)-androstene-3-one in place of 17cctrifluoromethylethynyl 17/8 hydroxy 19 nor 4 androstene-3-one there is obtained 17u-trifluor0methylvinyl- 19-nor-4-androstene-3-one-17fl-n-butyl ether, 17a-trifluorovinyl-l9-nor-4-androstene-3-one-l7 3-nbutyl ether, 17atrifluorovinyl 19 nor 5 (10) androstene 3 one-17B- n-butyl ether, 17a-trifluoromethylvinyl-19-nor-5 (10)-androstene-3-one-17/3-n-butyl ether and 17a-trifluoromethy1- ethynyl-19-nor-5 (10)-androstene-3-one-17[3-n-butyl ether.

In accordance with the above procedure but starting With any of the aforementioned 17fi-hydroxy androstenes and using methyl, ethyl, propyl, amyl, hexyl, cyclopentyl, cyelohexyl and benzyl iodide or bromide in place of n-butyl iodide there are obtained the corresponding 17;:- methoxy, 17/3-ethoxy, 17fi-propoxy, 17/8-amoxy, 17B- hexoxy, 17fl-cyclopentyloxy, l7 3-cyclohexoxy and 17fibenzyloxy androstenes.

EXAMPLE 9 To a mixture of 1 gm. of dimethyl sulfate in 10 ml. of N-sodiurn hydroxide is added a solution of 734 mg. of 17a trifluorovinyl 17 8 hydroxy l9 nor 4 androstene-3-one in 50 ml. of benzene. The mixture is then vigorously agitated for 18 hours at 20 C. At the end of this time the mixture may have formed an emulsion which is then reconstituted into its constituent parts by the addition of a small amount of ethanol and solid sodium chloride. The organic layer is then separated and the aqueous layer thoroughly extracted with benzene. The organic extract is then dried over potassium carbonate, filtered and the solvent removed 'by evaporation under reduced pressure. The residue is then chromatographed over acid Washed alumina and eluted with a mixture of ether and petroleum ether to give 17a-trifluorovinyl-19- nor-4-androstene-3-0ne-l7j3-methyl ether.

In accordance with the above procedure but starting with 170; trifluoromethylvinyl 17B hydroxy 19 nor- 4 androstene 3 one, 17a trifluoromethylethynyl- 17B hydroxy 19 nor 4 androstene 3 one, 170'.- trifiuorov inyl 175 hydroxy 19 nor (10) androstene-3-one, 17a-trifluoromethylviny1-17B-hydroxy-19-nor- 5 -androstene-3-one and 17a-trifluoromethylethynyl- 17 3-hydroXy-19-nor-5(10)-androstene-3-one in place of 170: trifiuorovinyl 17,8 hydroxy 19 nor 4 androstene-3-one there is obtained 17a-trifluoromethylvinyl-19- nor-4-androstene-3-one-17B-methyl ether, 17a-trifluoromethylethynyl 19 nor 4 androstene 3 one 175- methyl ether, 17a-trifluorovinyl-19-nor-5 (10)-androstene- 3-one-l7fi-methyl ether, 17a-trifluoromethylvinyl-19 nor- 5 (10) -andr0stene-3-one-17,B-methyl ether and 17a-trifluoromethylethynyl 19 nor 5(10) androstene 3 one- 17fi-methyl ether.

In accordance with the above procedure but starting with any of the aforementioned 17,3-hydroxyandrostenes and using diethyl, dipropyl, dibutyl, diamyl, dihexyl, dicyclopentyl, dicyclohexyl and dibenzyl sulfate in place of dimethyl sulfate there are obtained the corresponding 17,3-ethoxy, l7p3-propoxy, 175-butoxy, l7fl-amoxy, 17,8- hexoxy, 17fi-cyclopentyloxy, 17,8-cyclohexoxy, and 17,8- benzyloxy androstenes.

We claim:

1. 17a-substituted-17p-hydroxy-19-nor-5(10) androstene-3-one wherein the 17a-SllbStltll6I1t is an unsaturated fiuorohydrocarbon radical having 2 to 3 carbon atoms.

2. 17oz substituted-175-alkanoyl0xy-19-nor-5(10)-androstene-3-one wherein the substituent at l7oc is an unsaturated fluorohydrocarbon radical having from 2 to 3 carbon atoms.

3. Hut-substituted 175 cycloalkoxy-19-nor-5(10)-androstene-3 -one wherein the substituent at 17a is an unsaturated fluorohydrocarbon radical having from 2 to 3 carbon atoms.

4. Hut-substituted 17B alkoxy-19-nor-5(10)-androstene-3-one wherein the substituent at 170: is an unsaturated fiuorohydrocarbon radical having from 2 to 3 carbon atoms.

5. Nix-substituted 19 nor-5(10)-androstene-3-0ne- 17B unsaturated hydrocarbon ether wherein the substituent at 17a is an unsaturated fluorohydrocarbon radical having from 2 to 3 carbon atoms.

6. Nix-substituted 19 nor-5(10)-androstene-3-one- 17;? basic alkyl ether wherein the substituent at 17a is an unsaturated fiuorohydrocarbon radical having from 2 to 3 carbon atoms.

7. 17u-trifluoroviny1 17 3 acetoxy-19-nor-5(10)-androstene-3-one.

8. 17u-trifluoroviny1 17,3 hydroxy-19-nor-5(10)-androstene-3-one.

9. l7a-trifluoromethylethynyl 17p hydr0xy-19-nor- 5 (10) -androstene-3-one.

10. 17a-trifluoromethylethyny1 caproyloxy-19- nor-5 l0) -androstene-3 -one.

11. l7a-triflu0romethy1ethynyl 17/8 acet0Xy-19-nor- 4-androstene-3-one.

12. 17a-trifluoromethylethyny1 17p caproyl0xy-19- nor-4-androstene-3-one.

13. 17a-trifluorovinyl 1713 methoxy-19-nor-5(10)- androstene-B-one.

14. 17a-trifluoromethylethynyl 17,8 cyclopentoxy-l9- nor-5 10) -androstene-3-one.

1S. 17a-trifluoromethylethyny1 19 nor-5(10)-a11drostene-3 -one-17B-pyrrolidyl ethyl ether.

16. 17a-trifiuorovinyl 19 nor-5(10)-androstene-3- one-17 3-diethylaminoethyl ether.

17. 17 a-trifluoromethylethynyl 17,3 meth0xy-19-nor- 4-androstene-3-one.

18. 17a-trifluoromethylvinyl 19 nor-4-androstene-3- one-17,6-allyl ether.

19. 17a-t1ifiu0romethylethynyl 19 nor-4-androstene- 3-one-17fi-diethylaminoethyl ether.

OTHER REFERENCES Fried et al., Journal of the American Chemical Soc., vol. 83, November 1961, pages 4663-4664 relied on.

LEWIS GOTTS, Primary Examiner.

ELBERT L. ROBERTS, Assistant Examiner. 

15. 17A-TRIFLUOROMETHYLETHYNYL-19-NOR-5(10)-ANDROSTENE-3-ONE-17B-PYROLIDYL ETHYL ETHER. 